Cancer (Exam 2) Flashcards
controlled cell division and growth impact what
organ development during embryogenesis, tissue homeostasis, tissue repair, and remodeling
normal cells are restricted in
their capacity to divide and grow and will not survive indefinitely
cell cycle
series of events by which normal and cancer cells divide to produce new cells
what is the cell cycle very strict in?
very strictly regulated in healthy cells
5 phases of cell cycle
DNA replication (S phase)
cell division (M phase)
2 resting phases (G1 and G2)
non-dividing state (G0 phase)
m phase
cell division - cell divides
G1 phase
resting phase - cell grows in size and decides to commit to the cell cycle or remain in a resting state
S phase
DNA replication - cell synthesizes (duplicates) its DNA
G2 phase
resting phase - cell prepares to divide
G0 phase
non-dividing state - the cell stops dividing and may differentiate
what determines if the cycle should proceed?
integrated signal input from oncogenes and tumor suppressors
what is the cell cycle mainly composed of and its promotion?
cyclins and cdk’s (cyclin-dependent kinases) and promotes progression through each phase
when in normal state, what starts the cycle?
receiving an external signal to divide
ex: growth factor binding at cell surface
G1 phase progression
cdk4/cyclin D, cdk6/cyclin D
S phase progression
cdk2/cyclin E, cdk2/cyclin A
G2 phase oncogenes
cdk1/cyclin A
M phase oncogen
cdk1/cyclin B
cell cycle checkpoints
elaborate system of molecular events is in place in each phase to prevent progression if the cell is damaged or the environment is unfavorable for growth
M phase checkpoint
check for proper attachment of chromosomes to spindles
G1 phase checkpoint
check for environmental cues, growth factor signals, nutrient availability, DNA damage, restriction site: retinoblastoma protein
G2 phase checkpoint
check for cell size, damaged DNA, unreplicated DNA
S phase checkpoint
check for DNA damage, ensure all DNA is replicated
cell cycle regulation
controls regulated the rate of cell proliferation and growth and can cause cancer if they are mutated
oncogene
normally promotes cell cycle progression, can induce uncontrolled cell division if mutated,
-cdk’s and cyclins
-E2F
tumor suppressor
normally prevents cell cycle progression, can induce uncontrolled cell division if mutates
p16, p21, p27, p57
suppress CDK activity
p53
senses DNA damage and activates P21
pRb
suppresses E2F activity
what do growth factors activate?
the cell cycle when they bind to cell surface receptors
growth factors
stimulate proliferation of many different type of cells growth factors can have different effects in different cell types.
what do growth factors bind to?
specific receptors in the plasma membrane and activate signaling pathways and consist of kinases cascades
what happens when kinases cascades are phosphorylated?
they will phosphorylate (activate) another kinase
growth factor pathways
lead to activation of nuclear kinases and changes in gene transcription that cause cell survival and cell cycle progression
growth factor pathway components
Phospholipase C (PLC)/ Protein C (PKC)
PI3K/Akt
RAS/RAF/MEK/ERK
growth factor pathways from individual growth factors do what?
overlap and amplify a response to proliferate
mutated growth factor receptors and signaling proteins can trigger what?
uncontrolled cell division
inhibitory signaling pathways from other growth factors can..?
suppress a response to proliferate
what do normal cell division and growth rely on?
expression of proteins encoded in DNA
what is DNA expression regulated by?
epigenetics
what does wrapping DNA around histone proteins allow?
allows DNA to be compacted into chromosomes and can determine whether a gene will be expressed or not
enzymes that compact chromatin
DNMT: DNA methyltransferase
HDAC: histone deacetylase
enzymes that loosen chromatin
HAT: histone acetyltransferase
histone modifications
regulated by environmental factors (toxin exposure, smoking, alcohol, exercise, diet)
behaviors affect heritable patterns of gene expression via epigenetics
heterochromatin
tightly packed nucleosomes
gene is silenced
euchromatin
loosely packed nucleosomes
gene is expressed
why is a gene silenced?
methylation of DNA and histones causes nucleosomes to pack tightly together. transcription factors cannot bind the DNA, and genes are not expressed
why are genes expressed?
histone acetylation results in loose packing of nucleosomes. transcription factors can bind the DNA and genes are expressed
apoptosis
programmed cell death
normal process required for tissue homeostasis, also will kill cells that are abnormal
regulated by tumor suppressors and oncogenes
what can prevent apoptosis?
over-expression of oncogenes (Bcl-2)
cellular senescence
a cell stops growing and dies after a certain number of divisions
what are cellular senescences regulated by?
telomeres
telomeres
DNA sequence of caps at ends of chromosomes that protect ends of DNA from damage
shorten after each replication, once at a critical length cells senesce
telomerase
enzyme that adds DNA to telomeres - over expression can inhibit telomere shortening and prevent normal cell senescence
DNA repair
mechanisms composed of several enzymes that identify and repair damage to DNA
how can DNA be mutated?
by exposure to environmental factors (UV irradiation, cigarette smoke, X-rays) or by effects of normal cellular processes such as DNA replication
how many cells does the human body contain?
about 37 trillion cells, each cell having about 3 billion bases
mutation rate per cell
quite low
10-8 - 10-7 mutations per nucleotide per cell division
what does each cell in the body experience every day?
about 10,000 DNA lesions due to normal metabolic processes and environmental exposures; most of these lesions are repaired
DNA repair mechanism
detection of mutation
removal of mutated DNA (usually with some surrounding normal DNA)
re-synthesis of correct DNA using other strand in double helix: polymerases
sealing the ends of the newly synthesized DNA to the surrounding DNA: ligases
immune surveillance
human t cells can recognize cancerous cells as foreign
antigen presenting cells (APCs)
pick up antigens released from tumor cells APCs activate T cells to recognize tumor antigens. T cells find tumor cells and kill them
neoplasia
new or abnormal cell growth characterized by loss of tissue homeostasis and distorted architecture
benign tumor
abnormal cell growth confined to one specific tissue site; few systemic manifestations and no threat to overall state of healthc
cancer or malignant tumor
a more advanced form of neoplasia that involves tissue and damage; a progressive process that can culminate in systemic disease and death
tumor/neoplasm
growth resulting from disordered regulation of a cell cycle
what do most cancers show?
unlimited cell division and impaired differentiation
cancer biomarker
a gene or protein that is altered in expression in cancer and can be used to identify a type of cancer
cancer progression
characterized by an accumulation of genetic alterations that cause morphological changes in cells within a tissue
hypertrophy
enlargement of cells (too much protein and membrane)
hyperplasia
higher than normal cell division, causing crowding of cells
dysplasia
cells revert to an immature, less differentiated state, causing disordered growth
metaplasia
cells appear and function like cells of a different type
genotoxic agents
induce DNA mutations
non-genotoxic agents
do not induce DNA mutations, on their own, usually accelerate cell division in other ways
chemical carcinogens metabolic reactions
convert many carcinogens to highly reactive molecules that can react with nucleotides in DNA
DNA adduct disrupts structure of DNA helix
chemical carcinogens altered structure of DNA
adduct causes nucleotide to mispair during replication, resulting in a mutation that can be propagated to progency cells
ionizing radiation
very severe
can lead to chromosomal abnormalities
can also induce mutations and cell death
non-ionizing radiation
less severe
may stall replication and transcription
can also induce mutations
microbial carcinogens
pathogenic bacteria can induce carcinogenesis in several ways (direct and indirect)
altering intracellular signaling pathways
stimulate proliferation of human cells
induce chronic inflammation
product toxins and ROS that damage human DNA
trigger a stem cell-like phenotype
microbiome
composition of microbes in a tissue environment; often a critical factor in promoting or preventing tumorigenesis
how can viruses induce carcinogenesis?
stimulate uncontrolled proliferation of human cells by
expressing proteins that inactivate tumor suppressors and inhibit apoptosis
inserting in human genome near oncogenes and activating their expression: induce chronic inflammation, mutations by gene integration that interrupts DNA sequence
HPV proteins
E6 protein targets p53 for destruction
E7 protein sequesters Rb
spontaneous mutations
changes to DNA sequences that occurs in a cell without any known induction by an environmental mutagen
rate of spontaneous mutations in humans
1.4 x 10^8 mutations per nucleotide per cell generation
with about 6 million nucleotides in the human genome that means about 84 mutations in each cell per cell division
spontaneous mutations sources
errors in DNA replication
spontaneous lesions
transposable elements “jumping genes”
spontaneous mutations during replication
slippage of DNA polymerase at nucleotide repeats can cause strand misalignment and induce deletions or insertions
spontaneous mutations caused by DNA lesions
depurination: loss of purine base
deamination: change of cytosine to uracil
ROS
formed under high metabolic stress
can alter guanine so that it can pair with adenine
depurination and deamination result
result in incorporation of an incorrect nucleotide in the DNA sequence during replication
spontaneous mutations caused by transposons
DNA sequences encoding enzymes that, when expressed, cause the DNA sequence to be inserted into another location in the genome
can insert within a gene and disrupt its function, causing diseases including cancer
frequency of jumping
about 1 new insertion occurs in 10-100 live births
defects in DNA repair pathways
induce many gene mutations
- if mutations inactivate the function of important genes in these pathways, DNA damage will not be required
results in DNA repair pathways
many mutations (1000s) per cell this increases the chance that a cell will undergo carcinogenesis
chromosomal instability
condition whereby large segments of the genome may be gained, lost, or rearranged due to defects
chromosomal instability defects
replication and distribution of a full set of sister chromatids to daughter cells during mitosis
aneuploidy
having an abnormal number of individual chromosomes
structural rearrangements
alter gene function and expression
what can cancer result from?
mutations in DNA
point mutation
changing a single nucleotide to another
- silent mutation
- missense
- nonsense
silent mutation
no effect
missense
change amino acid
nonsense
premature stop codon
insertion or deletion
adding or removing 1 or more nucleotides
- frameshift mutation
frameshift mutation
changes reading frame of ribosome, alters all sequence afterward
what can lead to carcinogenesis?
if a mutation changes the function of a protein that controls cell proliferation of survival
genes that are known to be mutated in cancer
proto-oncogene
proto-oncogene
confers an advantage to tumor cells through a gain of function mutation
- less common because very specific mutations are required to activate function
proto-oncogene mutated form
oncogene
mutation of 1 out of 2 alleles is necessary to alter protein function
proto-oncogene activation
through mutation, gene amplification and overexpression, chromosomal translocation
tumor suppressor
confers an advantage to tumor cells through a loss of function mutation
- more common because can inhibit a proteins function or expression
tumor suppressor change in function
results from nonsense, missense, frameshift, and deletion/insertion mutations
without cell cycle control…
cancer cells continue to proliferate
- without growth inducing signals
- with damaged DNA
- without proper duplication and segregation of chromosomes
common oncogenes activated
ckd4/cdk6: activated in many cancers
cdk1
cyclin D
tumor suppressors inactivated
p53: 50% of cancers have this mutation
p16
what do mutated genes encode?
proteins that overactivate growth factor signaling pathways., causing them to be constitutively activated even in the absence of growth factor signal from the cell environment
examples of oncogenes in growth factor signaling pathways
EGFR
HER2
Ras
Raf
example of common tumor suppressor in growth factor signaling pathways
PTEN
what do cancer cells experience?
experiences that would usually trigger apoptosis like unrepaired DNA, metabolic stress, hypoxia
what do cancer cells disrupt?
apoptotic mechanisms and survive with accumulating damaged even with chemotherapy
Bcl-2
frequently overexpressed
p53
frequency mutated or deleted
telomere in healthy cells
telomeres shorten with every cell division
over time crisis point is reached where chromosome ends cant be replenished and cells eventually die
telomere in cancer cells
telomeres don’t shorten with every cell division chromosome ends are continually replenished, cells survive and grow uncontrollably.
telomerase
can lengthen telomeres normally expressed in germ cells and early embryonic cells and early embryonic cells not expressed much at all in somatic cells after birth
clinical phase of cancer
defined by recognition of overt malignancy by symptoms or physical exams
preclinical phase of cancer
usually unknown to pt, may be identified by screening interventions
- colon polyps, lumps in breast tissue
- usually harbor molecule genetic abnormalities and exhibit features of abnormal proliferation without demonstrating invasiveness
initiation
exposure of cells to carcinogens or errors in DNA synthesis that cause DNA mutations
selective growth advantage
a clonal population of abnormal cells can develop
what mutations have no effect?
b and c
what mutants select for growth advantage over normal cells?
a, d, and e
original mutation
cause increase in proliferation that leads to the possibility of more mutations
promotion
repeated exposure of carcinogens or other factors favor selective expansion of altered cells compared to normal ones
- they are reversible
how do promotions act?
through multiple ways to increase proliferation and or decrease apoptosis by changing gene expression
conversion or malignant transformation
changing a preneoplastic cell into one that expressed a malignant phenotype
progression
accumulation of further genetic and epigenetic changes that lead to increase proliferation
progression interactions
between tumor cells and surrounding normal stromal cells as well as between tumor cells and the extraceullular matrix
how long does it take cancer to develop?
decades
CIS carcinoma in situ
still has defined boarders, does not metastasize
germline mutation
a genetic alteration that is inherited and is present in every cell of the body
- transmitted to next generation
somatic mutation
genetic alteration that is not inherited and is not present in every cell of the body but is aquired during a person’s lifetime
- will not be transmitted to next generation
familial cancer syndromes
often caused by loss of function of proteins involved with DNA repair, causing an increase the mutation rate of the genome
- can increase risk of cancer
angiogenesis
growth of new blood vessels
remodel blood vessel network, occurs before adulthood and in wound healing ,menstrucal sycle, muscle growth and regeneration of organ lung
tumor angiogenesis
tumor induced growth of new blood vessels induced by cancer cells
what cells can induce their own blood supply?
cancer cells
angiogenic cytokines
induced by hypoxic environment in tumor
vascular endothelial growth factor
produced by tumor cells, induces proliferation of endothelial cells. target for many anti tumor therapies.
platelet derived growth factor
produced bu tumor cells and endothelial cells
fibroblast growth factor
produced by tumor cells
matrix metalloproteinases
remodel extraceullular matric, mady but stomach cells
